Glypican-3 (GPC3) is an oncofetal antigen that belongs to the glypican family of glycosyl-phosphatidylinositol-anchored heparin sulfate proteoglycans. Glypicans are characterized by a covalent linkage to complex polysaccharide chains called heparinsulphate glycosaminoglycans. Glypicans are involved in cell signaling at the cellular-extracellular matrix interface. (Sasisekharan et al., Nature Reviews I Cancer, Volume 2 (2002).) To date, six distinct members of the human glypican family have been identified. Cell membrane-bound Glypican-3 is composed of two subunits, linked by one or more disulfide bonds.
Glypican-3 is expressed in fetal liver and placenta during development and is down-regulated or silenced in normal adult tissues. Mutations and depletions in the Glypican-3 gene are responsible for the Simpson-Golabi-Behmel or Simpson dysmorphia syndrome in humans. Glypican-3 is expressed in various cancers and, in particular, hepatocellular carcinoma (“HCC”), melanoma, Wilm's tumor, and hepatoblastoma. (Jakubovic and Jothy; Ex. Mol. Path. 82:184-189 (2007); Nakatsura and Nishimura, Biodrugs 19(2):71-77 (2005).)
HCC is the third leading cause of cancer-related deaths worldwide. Each year, HCC accounts for about 1 million deaths. (Nakatsura and Nishimura, Biodrugs 19(2):71-77 (2005)). Hepatitis B virus, hepatitis C virus, and chronic heavy alcohol use leading to cirrhosis of the liver remain the most common causes of HCC. Its incidence has increased dramatically in the United States because of the spread of hepatitis C virus infection and is expected to increase for the next two decades. HCC is treated primarily by liver transplantation or tumor resection. Patient prognosis is dependent on both the underlying liver function and the stage at which the tumor is diagnosed. (Parikh and Hyman, Am J. Med. 120(3): 194-202 (2007).) Effective HCC treatment strategies are needed. It would thus be desirable to have available means and methods for targeting GPC3, preferably GPC3 expressed on tumor cells.
Methods of isolating and analyzing GPC3 as well as agents for the treatment of diseases and conditions associated with GPC3 have been described in WO 2009/012394, WO 2007/137170 or WO 2007/047291. However, no Glypican-3-binding protein having the features attendant to the proteins provided by present invention has been previously described.